Essential role of zyxin in platelet biogenesis and glycoprotein Ib-IX surface expression.
Actin Cytoskeleton
/ metabolism
Animals
Blood Platelets
/ metabolism
Bone Marrow
/ ultrastructure
Cell Adhesion Molecules
/ metabolism
Cell Differentiation
Cell Line
Cell Membrane
/ metabolism
Female
Fibrinogen
/ pharmacology
Humans
Lysosomes
/ metabolism
Male
Megakaryocytes
/ metabolism
Mice
Mice, Inbred C57BL
Microfilament Proteins
/ metabolism
Microtubules
/ metabolism
Mutant Proteins
/ metabolism
Phosphoproteins
/ metabolism
Platelet Count
Platelet Glycoprotein GPIb-IX Complex
/ metabolism
Protein Binding
/ drug effects
Proteolysis
Proteomics
RNA, Messenger
/ genetics
Thrombin
/ pharmacology
Thrombocytopenia
Zyxin
/ deficiency
Journal
Cell death & disease
ISSN: 2041-4889
Titre abrégé: Cell Death Dis
Pays: England
ID NLM: 101524092
Informations de publication
Date de publication:
16 10 2021
16 10 2021
Historique:
received:
22
03
2021
accepted:
28
09
2021
revised:
15
09
2021
entrez:
17
10
2021
pubmed:
18
10
2021
medline:
3
2
2022
Statut:
epublish
Résumé
Platelets are generated from the cytoplasm of megakaryocytes (MKs) via actin cytoskeleton reorganization. Zyxin is a focal adhesion protein and wildly expressed in eukaryotes to regulate actin remodeling. Zyxin is upregulated during megakaryocytic differentiation; however, the role of zyxin in thrombopoiesis is unknown. Here we show that zyxin ablation results in profound macrothrombocytopenia. Platelet lifespan and thrombopoietin level were comparable between wild-type and zyxin-deficient mice, but MK maturation, demarcation membrane system formation, and proplatelet generation were obviously impaired in the absence of zyxin. Differential proteomic analysis of proteins associated with macrothrombocytopenia revealed that glycoprotein (GP) Ib-IX was significantly reduced in zyxin-deficient platelets. Moreover, GPIb-IX surface level was decreased in zyxin-deficient MKs. Knockdown of zyxin in a human megakaryocytic cell line resulted in GPIbα degradation by lysosomes leading to the reduction of GPIb-IX surface level. We further found that zyxin was colocalized with vasodilator-stimulated phosphoprotein (VASP), and loss of zyxin caused diffuse distribution of VASP and actin cytoskeleton disorganization in both platelets and MKs. Reconstitution of zyxin with VASP binding site in zyxin-deficient hematopoietic progenitor cell-derived MKs restored GPIb-IX surface expression and proplatelet generation. Taken together, our findings identify zyxin as a regulator of platelet biogenesis and GPIb-IX surface expression through VASP-mediated cytoskeleton reorganization, suggesting possible pathogenesis of macrothrombocytopenia.
Identifiants
pubmed: 34657146
doi: 10.1038/s41419-021-04246-x
pii: 10.1038/s41419-021-04246-x
pmc: PMC8520529
doi:
Substances chimiques
Cell Adhesion Molecules
0
Microfilament Proteins
0
Mutant Proteins
0
Phosphoproteins
0
Platelet Glycoprotein GPIb-IX Complex
0
RNA, Messenger
0
Zyxin
0
vasodilator-stimulated phosphoprotein
0
Fibrinogen
9001-32-5
Thrombin
EC 3.4.21.5
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
955Subventions
Organisme : National Natural Science Foundation of China (National Science Foundation of China)
ID : 81820108003
Informations de copyright
© 2021. The Author(s).
Références
Blood. 2016 Feb 4;127(5):626-36
pubmed: 26585954
Curr Protoc Immunol. 2016 Feb 02;112:22F.6.1-22F.6.15
pubmed: 26836510
J Biol Chem. 1998 Jan 30;273(5):3013-20
pubmed: 9446615
Curr Opin Cell Biol. 2007 Aug;19(4):453-8
pubmed: 17616384
Am J Hum Genet. 2013 Mar 7;92(3):431-8
pubmed: 23434115
Blood. 1988 Dec;72(6):1968-77
pubmed: 3196874
Hematology Am Soc Hematol Educ Program. 2017 Dec 8;2017(1):385-399
pubmed: 29222283
J Cell Biol. 2006 Feb 27;172(5):771-82
pubmed: 16505170
J Thromb Haemost. 2016 Jun;14(6):1268-84
pubmed: 26991240
J Biol Chem. 1992 Jun 25;267(18):12851-9
pubmed: 1618785
Blood. 2016 Jun 9;127(23):2903-14
pubmed: 26912466
Blood. 2012 Oct 4;120(14):2787-95
pubmed: 22653973
J Thromb Haemost. 2019 Sep;17(9):1430-1439
pubmed: 31220402
Hum Mutat. 2014 Sep;35(9):1033-45
pubmed: 24934643
J Biol Chem. 2000 Jul 21;275(29):22503-11
pubmed: 10801818
Mol Biol Cell. 2012 May;23(10):1846-59
pubmed: 22456508
Blood. 2011 Aug 25;118(8):2285-95
pubmed: 21652675
Blood. 2015 Jul 23;126(4):520-30
pubmed: 25964668
Blood. 2009 Jan 8;113(2):458-61
pubmed: 18849486
J Cell Biol. 2013 Jun 10;201(6):785-96
pubmed: 23751492
Am J Pathol. 1984 Sep;116(3):514-22
pubmed: 6383063
Blood. 2013 Oct 31;122(18):3178-87
pubmed: 23861250
Blood. 2007 Oct 1;110(7):2371-80
pubmed: 17515402
J Biol Chem. 1998 Nov 20;273(47):31449-54
pubmed: 9813057
Anticancer Res. 2020 Nov;40(11):5981-5988
pubmed: 33109535
J Cell Biol. 1999 Dec 13;147(6):1299-312
pubmed: 10601342
Haematologica. 2016 Jan;101(1):46-56
pubmed: 26452979
Nat Cell Biol. 2001 Aug;3(8):699-707
pubmed: 11483954
Trends Cell Biol. 2014 Oct;24(10):575-83
pubmed: 24933506
J Biol Chem. 2001 Sep 7;276(36):33328-35
pubmed: 11423549
J Biol Chem. 1996 Dec 6;271(49):31470-8
pubmed: 8940160
J Biol Chem. 1999 Aug 13;274(33):23549-57
pubmed: 10438535
Nat Med. 2004 Jan;10(1):64-71
pubmed: 14702636
Blood. 2014 Feb 6;123(6):921-30
pubmed: 24152908
Dev Cell. 2010 Sep 14;19(3):365-76
pubmed: 20833360
Mol Cell Biol. 2003 Jan;23(1):70-9
pubmed: 12482962
J Clin Invest. 2017 Mar 1;127(3):814-829
pubmed: 28134622
Blood. 2011 Nov 24;118(22):5928-37
pubmed: 21960593
Curr Opin Hematol. 2010 Sep;17(5):405-10
pubmed: 20601875
Haematologica. 2009 Jun;94(6):800-10
pubmed: 19377075
PLoS One. 2017 Mar 9;12(3):e0171728
pubmed: 28278518
Blood. 2018 Feb 8;131(6):686-698
pubmed: 29208598
Gene. 2018 Jul 20;664:152-167
pubmed: 29679756
Nat Commun. 2017 Mar 03;8:14639
pubmed: 28256511
Biochem Biophys Res Commun. 2004 May 28;318(2):439-43
pubmed: 15120620